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The role of systemic inflammatory markers, including C-reactive protein (CRP), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), in predicting survival for patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy (mTT) after first-line tyrosine kinase inhibitor failure remains unclear. Thus, we investigated the relationship between systemic inflammation and survival in such patients.Sixty-three patients were evaluated. Progression-free survival (PFS) and overall survival (OS) after second-line mTT initiation were evaluated according to the inflammatory marker levels. In addition, the prognostic factors for survival were examined.The receiver operating characteristic curves for CRP, NLR, and PLR had areas under the curve of 0.779, 0.619, and 0.655, respectively; no significant differences were noted. The corresponding cutoff values were 0.48, 2.53, and 183. Patients with higher CRP (n = 40), NLR (n = 32), and PLR (n = 22) levels had significantly lower PFS and OS than those with lower CRP, NLR, and PLR levels. Multivariate analyses showed that CRP was the sole independent predictor for PFS and OS.Systemic inflammation is associated with survival after second-line mTT. In particular, CRP was a strong independent predictive biomarker of prognosis.We evaluated the relationship between systematic inflammatory markers (C-reactive protein, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio) and survival in a cohort of 63 patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy after first-line tyrosine kinase inhibitor failure. Each marker was associated with progression-free and overall survival. In particular, C-reactive protein was a strong independent predictive biomarker of prognosis.